Schizophrenia (SZ) is undoubtedly etiologically heterogeneous with contribution to risk from both genetic and non-genetic factors. The identification of etiologically more homogeneous groups is important to developing our knowledge about the multiple pathophysiological pathways that are associated with SZ etiology. In this study, we will examine SZ etiology from a new perspective by incorporating data on individual exposure to Toxoplasma gondii (Toxo), a well supported SZ risk factor, into our existing genome-wide association analysis (GWAS) of SZ susceptibility. In addition, we will also be able to explore the relationship between Toxo exposure and the risk for bipolar disorder (BP). Hypotheses will be tested in a case-control study of Ashkenazi Jewish (AJ) individuals who are currently enrolled in studies at the Johns Hopkins University. Subjects include the following: 1) AJ SZ (N = 537) and BP (N =452) cases;2) parents of AJ SZ and BP cases (both parents are available for 254 SZ cases and 288 BP cases;total N = 1,084) and 3) AJ screened controls (N = 356). A wealth of clinical and biological data currently exists for these individuals, including plasma samples allowing for the assessment of Toxo IgG antibody titers. Several novel and statistically well- powered hypotheses will be tested in addition to groundbreaking exploratory analysis. We will determine if SZ individuals who have been exposed to Toxo differ clinically from those who have not. Specifically, we plan to explore Toxo serological exposure indices and our extensive data on psychiatric symptom domains to determine whether particular symptom domains distinguish SZ accompanied by Toxo infection versus SZ in which Toxo is not a factor. We plan to ascertain Toxo exposure in the mothers of SZ probands to explore the concept that gestational infection may be a factor connecting Toxo with SZ risk. We will use our existing GWAS data on the SZ patients and screened control subjects to test the hypothesis that SZ is associated with genetic variants in pathways related to Toxo infection and neuroimmune responses. We will further examine the role of 25 positional or functional candidate genes for SZ in the context of Toxo exposure, and determine whether these genes act as effect modifiers in the connection between Toxo infection and SZ risk. We will explore the relationships between Toxo infection and SZ on a whole genome basis, and place this data into pathophysiological context using pathway-based bioinformatics. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic psychiatric disorder that affects 1% of the population worldwide and involves both biological and environmental factors. Previous research has demonstrated that individuals diagnosed with schizophrenia have a higher rate of exposure to an infection caused by Toxoplasma gondii (a protozoan parasite) than individuals who are not diagnosed with schizophrenia. In this study, we will focus on individuals of Ashkenazi Jewish descent, a relatively homogeneous population and test several research questions regarding the relationship between toxoplasma exposure and the risk for schizophrenia but also its possible role in bipolar disorder.